We will determine the sites, developmental stages and mechanisms of B cell tolerance to the self-antigens that are the targets of Lupus and rheumatoid arthritis autoantibodies. For this purpose we have developed mice with transgenes coding for anti-DNA and rheumatoid factor derived from diseased mice. These transgenic mice have shown that self-reactive B cells can be regulated at different stages of B cell development and by different mechanisms. We will now study the germline precursors to these pathologic autoantibodies; how they are regulated and how they contribute to the autoimmune response. We will study new models of mutated, high affinity anti-DNA to understand the mechanism of receptor editing. We will study new transgenic models of autoimmunity in which autoantibodies arise spontaneously. These models provide a way of identifying the antigens that activate autoreactive B cells. We will determine how anti-DNA binds to autoantigen and how receptor editors prevent binding. This will allow the design of ligands that interfere with binding or induce tolerance mechanisms. Our goals are to know how autoantibodies are induced and what the checkpoints are that prevent their induction in healthy individuals. Comparison of transgene regulation in healthy mice to autoimmune mice will identify which mechanisms of regulation fail in systemic autoimmune diseases.